Early effects of diabetes on inducible nitric oxide synthase in the kidney.

NO may be responsible for the glomerular hyperfiltration observed in diabetic kidney by inducing vasodilation of the afferent arteriole. The aim of this study was to evaluate which isoform of nitric oxide synthase (NOS) is responsible for increased renal production of NO in diabetic kidney. Thirty male WKY rats were divided into 6 groups. Five rats were sacrificed immediately, five after 20 days. In the other rats, diabetes was induced by streptozotocin. The four diabetic groups were sacrificed respectively after 5, 10, 15 and 20 days. Urine excretion of NO metabolites was assayed; immunochemistry showed the presence of inducible (iNOS) and endothelial constitutive (ecNOS) synthases in the kidney. Urinary excretion of NO metabolites increased significantly in diabetic rats five days after the induction of diabetes and at the end of the study whereas it was unchanged in the control group. Renal ecNOS remained unchanged throughout the study in all rats whereas iNOS increased significantly in diabetic rats from the fifth day until the end of the study. The results demonstrate that iNOS is activated in the kidney of rats, soon after the induction of diabetes, thus suggesting its involvement in the increased production of NO observed immediately after the onset of diabetes.

Lacidipine reduces high blood pressure and the target organ damage induced by high fructose diet in rats.

OBJECTIVE: Normotensive rats fed a high fructose diet (HFD) develop hypertriglyceridemia, hyperinsulinemia and hypertension. The glomerular changes observed in the kidneys of these animals are similar to those observed in diabetic rats. The aim of this study was to evaluate whether lacidipine could be effective not only in preventing, but also in inducing the regression of hypertension, and renal and cardiac damage in rats fed HFD. METHODS: Thirty male Wistar-Kyoto (WKY) rats received HFD for 1 month; thereafter, five rats were sacrificed (Group 1) and the other 25 rats were divided into three groups: Group 2 (five rats) received HFD plus placebo, Group 3 (10 rats) HFD plus lacidipine 3 mg/kg per day, and Group 4 (10 rats) HFD plus hydralazine 10 mg/kg per day. At the end of the second month all animals were sacrificed. Kidneys and hearts were immediately removed. Renal deposits of collagen I, collagen IV, fibronectin and cardiac deposits of collagen III were assessed by means of immunohistochemistry. RESULTS: In the rats receiving HFD plus placebo, blood pressure was increased after the first and the second month of diet. This increase was reversed by lacidipine and hydralazine but, although both drugs normalized blood pressure, only lacidipine was effective in reducing renal and cardiac damage. CONCLUSIONS: These data suggest that lacidipine is effective in reversing hypertension and reducing target organ damage induced by HFD. Moreover, this protective effect on target organs appears to be not simply a consequence of blood pressure reduction, but seems to be connected to the type of hypotensive drug administered.

Antihypertensive drugs and the nervous system: ACE-inhibitors restore oscillatory potentials in hypertensives.

The authors have previously reported that oscillatory potentials (O.P.) of the electroretinogram are impaired in essential hypertensive patients before the appearance of funduscopic changes. They can therefore be considered an early marker of the nervous damage induced by hypertension. Aim of this study was to evaluate whether an antihypertensive regimen could influence the progression of this damage. O.P. were recorded in 35 essential hypertensives before antihypertensive treatment and after one-year treatment. The patients were randomly allocated into 4 treatment groups: 1) beta-blockers 2) ACE-Inhibitors 3) calcium antagonists 4) no pharmacological treatment. At the end of the study, blood pressure was significantly decreased in all but group 4. O.P., similar in the 4 groups at the beginning, were significantly higher at the end of the study only in patients treated with ACE-inhibitors. The results of this study suggest that although all hypotensive agents reduced blood pressure only ACE-I showed a protective effect on the retinal electric electrophysiology in hypertensive patients.

Lacidipine prevents the hypertension and renal and cardiac changes induced by high-fructose diet in WKY rats.

Normotensive rats fed a high-fructose diet (HFD) develop hypertriglyceridemia, hyperinsulinemia, and hypertension. The glomerular changes observed in the kidneys of these animals are similar to those observed in diabetic rats. The aim of this study was to evaluate whether lacidipine, a calcium antagonist, could have a protective effect with this animal model. Forty male Wistar-Kyoto (WKY) rats were divided into four groups treated with HFD + placebo; HFD + lacidipine, 0.3 mg/kg/day; HFD + lacidipine, 3 mg/kg/day; or standard diet + placebo for 4 weeks. Urinary excretion of the stable metabolic products of nitric oxide (NO) was determined, because this vasoactive agent has been found to cause hemodynamic changes in the diabetic kidney. Glomerular size was determined by means of morphometric analysis. The results of this study show that lacidipine prevents (a) the HFD-induced increase in blood pressure in a dose-dependent manner; (b) the HFD-induced increase in glomerular size and fibronectin synthesis; and (c) the increase of collagen III synthesis in the heart. The drug had no effect on the increased urinary excretion of the stable metabolic products of NO. These data suggest that lacidipine might be useful in preventing the renal and cardiac damage caused by hypertension and non-insulin-dependent diabetes mellitus.

Bosentan reduces blood pressure and the target-organ damage induced by a high-fructose diet in rats.

BACKGROUND: Rats fed a high-fructose diet develop hyperinsulinaemia, hypertriglyceridaemia, hypertension, renal changes similar to those in diabetic rats and left ventricular hypertrophy with deposition of collagen. Bosentan is an antagonist of endothelin receptors. Other authors have demonstrated that bosentan is effective in preventing the increase in blood pressure induced by a high-fructose diet but, until now, the effect of the drug on the target organs has not been investigated. OBJECTIVE: To evaluate whether bosentan is effective, not only in reducing blood pressure, but also in limiting the renal and cardiac changes induced by a high-fructose diet METHODS: Forty Wistar-Kyoto (WKY) male rats were divided into four groups: groups 1 and 2 received a high-fructose diet, groups 3 and 4 received a standard diet for 1 month. Thereafter, the following treatments were administered: group 1, high-fructose diet plus bosentan 100 mg/kg per day; group 2, high-fructose diet plus placebo; group 3, standard diet plus bosentan 100 mg/kg per day; group 4, standard diet plus placebo. After a further 1 month, all animals were killed. A morphometric analysis was performed by examining 100 glomeruli for each animal. Renal deposits of collagen and fibronectin and cardiac deposits of collagen III were measured by means of immunochemistry. RESULTS: By the end of the study, bosentan had completely reversed the increase in blood pressure induced by a high-fructose diet, without modifying the blood pressure in normotensive rats. Moreover, bosentan reduced glomerular hypertrophy and deposits of collagen and fibronectin in the kidney and cardiac deposits of collagen III. CONCLUSIONS: The results of this study demonstrate that bosentan not only normalizes blood pressure, but also protects target organs in rats receiving a high-fructose diet.

Oscillatory potentials of the electroretinogram in hypertensive patients with different antihypertensive treatment.

Oscillatory potentials of the electroretinogram are useful to confirm the diagnosis of essential hypertension. Thirty-five hypertensive patients underwent primary antihypertensive therapy with four different treatments. Oscillatory potentials were recorded before the treatment and after 12 months. The oscillatory response increased in a statistically significant manner in the angiotensin-converting enzyme inhibitor group. This is probably caused by the vasodilatation mechanism, which increases the retinal blood flow.

Follow up of young people with high casual blood pressure.

High blood pressure (BP), often borderline hypertension, can be also found in adolescents. In these subjects the haemodynamic pattern, high cardiac output and normal vascular resistance, differs from that of older hypertensives. Although the risk for hypertension is higher in this group than in the general population, only a minority of them will develop sustained hypertension later in life. They can therefore be viewed as an enriched pool of future hypertensives but not as true prehypertensives. The aim of this longitudinal study was to analyse the relation between casual BP measured in high school students and in the same subjects 3 years later. In 1990, an extensive study on BP was carried out in 1062 high school students aged 18 years. Sitting BP, heart rate, weight, and body mass index (BMI) were measured in each subject. After 3 years, the 50 subjects with the highest BP level recorded in 1990 were recalled. Forty-five subjects (90%, 30 males and 15 females) agreed to undergo a second examination. They were seen as outpatients in the Hypertension Centre of our institute. BP was measured with a mercury sphygmomanometer after a 10 min rest three times in 5 min. Systolic and diastolic BP were significantly reduced after 3 years (137 +/- 13 vs 132 +/- 10 P = 0.002; 92 +/- 4 vs 85 +/- 6 P = 0.0001, mm Hg). By means of a multiple regression test, including parameters recorded in 1990, systolic blood pressure (SBP) (R = 0.53 Slg F = 0.0002) and diastolic blood pressure (DBP) (R = 0.60 Slg F = 0.0001) were shown as the main determinants of SBP, while DBP was related only to previous BMI (R = 0.37 Slg F = 0.01). The reduction of both SBP and DBP after 3 years could be explained either by a true, spontaneous decrease of BP or as a consequence of different environmental conditions during the second examination (more prolonged resting time, repeated measurements). However, data of this study demonstrate that casual SBP and DBP are the main determinants of future SBP, thus confirming the prognostic value of casual BP measurement in young people. Moreover, our data emphasises the role of BMI as the main determinant of future high DBP.

Neither physical exercise nor alpha 1- and beta-adrenergic blockade affect plasma endothelin concentrations.

Endothelins (ET) are recently discovered vasoconstrictor agents released from endothelial cells and have been the object of intense investigation by researchers. Many of the factors that seem to influence the release of ET are modified by prolonged exercise. The purpose of this study was to investigate the effect of physical exercise on ET plasma concentrations and the effect of alpha- and beta-blockade on ET concentrations at rest and during exercise. Fifteen young volunteers (age 20-35 years) performed an exercise test on a bicycle ergometer. The starting workload of 50 W was increased by 30 W every 3 min until maximal heart rate was achieved; after a 2 min recovery period at 50 W the test continued for 15 min at 60% maximal work load. Blood samples were taken for ET determination before and after the test. After 1 week, the test was repeated. In the 2 days before either the first or the second test, each volunteer randomly received carvedilol (C) (25 mg), an alpha 1-adrenoceptor and beta-adrenoceptor blocker. There was no significant difference in ET concentrations after exercise with or without C administration (1.24 +/- 0.66, 1.42 +/- 0.83, 1.66 +/- 1.15, 1.61 +/- 0.87 pg/mL), showing that prolonged aerobic exercise does not affect plasma ET levels. Moreover, in our healthy young volunteers, blockade of alpha- and beta-adrenoceptors had no effect on ET levels at rest and after exercise.

Effects of chronic treatment with losartan on blood pressure, endothelin-like immunoreactivity and nitric oxide in normotensive rats.

BACKGROUND: Losartan is a new angiotensin II type 1 (AT1) receptor antagonist and an antihypertensive drug. Nitric oxide is a vasodilating agent and endothelins are powerful vasoconstrictors, both synthesized by and released from endothelial cells. Angiotensin II promotes the release of endothelins in cultured cells and this effect is prevented by losartan. Nitric oxide is also synthesized in the macula densa; therefore this substance may affect the regulation of renin excretion. OBJECTIVE: The aim of the present study was to evaluate the effects of losartan on blood pressure, endothelin-like immunoreactivity and nitric oxide in normotensive rats. MATERIALS AND METHODS: Male Wistar-Kyoto rats were divided into two groups. One group (n = 10) was treated with losartan at 10 mg/kg once a day by gavage for 4 weeks and a placebo group (n = 10) was given the same volume of water once a day by gavage. Blood pressure was measured weekly with a tail cuff and 24-h urine was collected at the beginning and at the end of the study. After 4 weeks all rats were killed and blood samples taken. Endothelin-like immunoreactivity was determined in plasma and urine using a 125I endothelin radioimmunuoassy kit. The stable metabolic products of nitric oxide, NO2- and NO3-, were measured in urine by the brucine method. RESULTS: After 4 weeks blood pressure was significantly lower in the losartan group (131 +/- 4 versus 118 +/- 6 mmHg, P = 0.001). Plasma endothelin-like immunoreactivity was similar in both groups while 24-h urinary endothelin-like immunoreactivity was significantly increased in the losartan group (29 +/- 25, 32 +/- 21, 43 +/- 19, 72 +/- 30 pg/24 h; F = 0.0003). NO2- and NO3- were unchanged in both groups. CONCLUSIONS: Our data show that chronic AT1 receptor blockade does not modify plasma endothelin-like immunoreactivity but increases urinary endothelin-like immunoreactivity. The significance of this finding remains obscure. It may represent a compensatory mechanism against the sustained vasodilation caused by losartan. Nitric oxide does not seem to affect the antihypertensive effect of losartan, since the urinary excretion of nitric oxide metabolites was unchanged.

Nifedipine reduces postexercise proteinuria in young volunteers.

Previous studies have demonstrated that it is possible to prevent postexercise proteinuria with angiotensin-converting enzyme inhibitors. To determine whether calcium antagonists have the same effect, 40 young healthy volunteers underwent maximal aerobic exercise with and without nifedipine 10 mg per os 1 h before the first or second trial. Urinary excretion of albumin (UAE), transferrin (UTE) and alpha 1-microglobulin (UME) were examined before and after each trial. UAE, UTE and UME were significantly increased after exercise. Nifedipine significantly decreased UAE (p = 0.001) and UTE (p = 0.02) after exercise, and slightly decreased the maximal work load and the basal excretion of albumin. UME was unchanged. Therefore, the results of this study demonstrate that nifedipine administration before exercise significantly reduces postexercise proteinuria.

Oscillatory potentials of the electroretinogram in hypertensive patients.

Because alteration of oscillatory potentials of the electroretinogram has been described in diabetic patients without signs of diabetic retinopathy as an early marker of changes in microcirculation, we studied the behavior of these potentials in patients with early-onset hypertension. Electroretinograms were recorded in 24 subjects with essential hypertension (blood pressure > 140/90 mm Hg) and in 9 age-matched normotensive control subjects (blood pressure < 140/90 mm Hg). Diabetes and ocular diseases were considered exclusion criteria. Sitting blood pressure was measured by a single investigator with a mercury sphygmomanometer after each subject had been at rest for 10 minutes. Funduscopic changes in all subjects did not exceed stage I World Health Organization classification. The oscillatory index was calculated by adding waves O1, O2, and O3 within the b wave of the electroretinogram. Statistical analysis was performed with Student's t test for paired and unpaired data and linear regression. The oscillatory index was significantly reduced in hypertensive patients compared with normotensive subjects. An inverse relationship was observed when systolic and diastolic blood pressures were plotted against the oscillatory index. In conclusion, our data demonstrate that the electrical activity of the retina is altered early in the course of hypertension and that the influence of systolic pressure on the oscillatory index is greater than that of diastolic pressure.

Metabolic effects of atenolol and doxazosin in healthy volunteers during prolonged physical exercise.

Nonselective beta-blockers may reduce exercise performance, not only through hemodynamic but also through metabolic effects. During prolonged physical exertion, lipolysis induced by plasma epinephrine occurs through beta-adrenoceptors of adipocytes. Therefore, beta-blockade may reduce release of free fatty acids (FFA) from adipocytes and consequently the energy supply for muscle cells. In this single-blind study, we compared the metabolic effects of atenolol with those of doxazosin, an alpha 1-blocker, during exercise in 26 young volunteers (age 20-35 years). All subjects performed an exercise test on a bicycle ergometer 5 h after consuming a standard breakfast. The starting workload of 50 W was increased by 30 W every 3 min until maximal heart rate (HR) was achieved; after a 2-min recovery period at 50 W the test was continued for 15 min at 60% maximal workload. Before and at the end of the test, blood samples were taken for glucose, lactate, and FFA determination. After 1 week, the test was repeated; the volunteers randomly received atenolol or doxazosin for 2 days before the second test. Exercise performance, plasma glucose, and lactate were not affected by either drug. The concentration of FFA was unchanged in subjects treated with doxazosin but was significantly reduced after the test in subjects treated with atenolol. Our data demonstrate that neither doxazosin nor atenolol impairs exercise performance in young volunteers. Atenolol reduces plasma FFA concentration possibly by inhibiting lipolysis. Doxazosin, in contrast, does not alter this parameter. Therefore, doxazosin may be a antihypertensive drug of potential benefit in treatment of hypertensive patients engaging in sports or undergoing a program of physical training.(ABSTRACT TRUNCATED AT 250 WORDS)

Oscillatory potentials in subjects with treated hypertension.

Oscillatory potentials of the ERG proved to be a sensitive indicator even in mild disturbances of retinal circulation, such as the first stage of hypertensive retinopathy (WHO classification). Oscillatory indexes (OIs) and blood pressure levels of 24 hypertensive patients in stage 1 of the WHO classification, who underwent an antihypertensive therapy for the first time, were considered. The patients were retested after a mean period 8 months. a strict inverse correlation was found between OIs and blood pressure levels.

Doxazosin versus nitrendipine: a double-blind comparative study in patients adhering to a sodium-restricted diet.

The aim of this double-blind parallel-group study was to compare the effects of doxazosin, a selective alpha 1-adrenoceptor antagonist with a long plasma half-life, with nitrendipine, a long-acting calcium-entry blocking drug. Following a 4-week placebo period, 26 patients with mild-to-moderate essential hypertension were randomly allocated to treatment with either doxazosin (n = 12) or nitrendipine (n = 14). Over a period of 10 weeks, doses were titrated to obtain a standing diastolic pressure below 90 mmHg. Thereafter, optimal doses were continued for another 4 weeks. Both drugs were administered once daily; median doses were 4 mg/day for doxazosin and 10 mg/day for nitrendipine. During the titration period three patients in the doxazosin group and one in the nitrendipine group dropped out from the study; one patient on doxazosin was considered a nonresponder. Twenty-one patients completed the study. The percentage of patients showing an adequate hypotensive effect (standing diastolic pressure below 90 mmHg) at the end of the study was similar in the two groups (42% vs. 50% in the intention-to-treat analysis and 56% vs. 54% in the per-protocol analysis). Casual, basal, and standing blood pressure and heart rate did not differ between groups throughout the study; serum lipids and blood glucose remained unchanged. We conclude that doxazosin and nitrendipine given as monotherapy are equally effective in mild to moderate hypertension.

Involvement of the renin angiotensin system in the pathogenesis of postexercise proteinuria.

Proteinuria after strenuous exercise is common in healthy subjects. The pathophysiologic mechanism of postexercise proteinuria (PEP) is not clear, although the phenomenon has long been known and many explanatory theories have been proposed. It is widely recognized that angiotensin II may increase filtration of protein through the glomerular membrane, and that its concentration in plasma increases during exercise. The aim of this study was to evaluate possible involvement of angiotensin II in the pathogenesis of PEP. Of 25 young volunteers who performed maximal aerobic exercise, eight showed PEP. The exercise was repeated after an interval of at least one week, now 90 minutes after administration of captopril (25 mg). Captopril did not affect the achieved work load of the maximal blood pressure and heart rate during the exercise, but PEP was not found. As it was possible to prevent PEP by administering an angiotensin-converting enzyme inhibitor, the study supports the theory that the renin angiotensin system is involved in the pathogenesis of PEP.

[Comparative assessment of arterial blood pressure and body composition in athletes practicing physical culture and in obese subjects]. / Valutazione comparativa della pressione arteriosa e della composizione corporea in atleti praticanti cultura fisica ed in soggetti obesi.

The relationship between body weight excess and hypertension has been widely demonstrated. Some body-builders can reach an important body weight excess because of the skeletal muscle hypertrophy; their body mass index is comparable to that of obese subjects, although body fat excess is responsible for overweight in the latter. Blood pressure, fasting plasma glucose and insulin, Na+, K+, Ca++ urinary excretion have been compared in three groups of young males: 1. body builders with BMI greater than 27; 2. obese subjects with BMI greater than 27; 3. normal subjects with BMI less than 25. Systolic blood pressure was similar in body-builders and obese and significantly higher than in the control group. Diastolic blood pressure, fasting plasma glucose and insulin were similar in normal subjects and in body-builders and significantly lower than in obese subjects. Although our results confirm the relationship between increased diastolic blood pressure, hyperinsulinemia and body fat excess, the finding of increased systolic blood pressure suggests caution in body-building, because systolic hypertension has been demonstrated to be a risk factor for vascular diseases.

[Arterial hypertension and the kidney in pregnancy]. / Ipertensione arteriosa e rene in gravidanza.

Hypertension complicates approximately 10 per cent of all pregnancies and accounts for 20% of all maternal deaths. Blood pressure normally decreases in the first trimester of pregnancy, secondary to a decrease in peripheral vascular resistance, reaches its lowest point in the second trimester and then gradually increases to or near pregravid levels at term. Normal pregnant women develop vascular resistance to the pressor effect of angiotensin II, which is precociously lost in women who develop gestational hypertension. Prostaglandins seem to be involved in the development of this vascular refractoriness. An acute and reversible lesion--defined "Glomerular endotheliosis"--has been described as the basic pathologic pattern of pre-eclamptic nephropathy, although gestational hypertension can be superimposed on undiagnosed essential hypertension or any of a variety of renal diseases. The primary goal when treating gestational hypertension is successful termination of the pregnancy with the least trauma to mother and fetus. Antihypertensive drugs could be administered to prolong pregnancy when this is considered desirable, although pharmacological therapy of gestational hypertension remains a subject for dispute, because of the lack of closely controlled studies. Hydralazine and methyldopa are drugs with a long history of use in gestational hypertension. Beta-blockers have been shown to be as effective as methyldopa. Clinical experience with nifedipine is limited, but controlled clinical trials, currently in progress, suggest its suitability.

ACE inhibitors: antihypertensive treatment and renal function.

Much clinical evidence supports the use of angiotensin-converting enzyme inhibitors (ACE-I) as the first-step drugs in the treatment of essential hypertension. The acute and chronic effects of ACE-I on renal function are reviewed in this paper. The kidney is an important target organ of essential hypertension and some antihypertensive drugs have been shown to decrease renal haemodynamic parameters. In hypertensives with normal renal function, ACE-I were demonstrated to be safe drugs: after acute and chronic administration of these drugs, the drop in blood pressure was accompanied by unchanged or increased GFR and RPF, with decreased renal vascular resistance. Only in patients with renovascular hypertension, with bilateral stenosis or solitary kidney, was there a deterioration in renal function.

[Correlations between calciuria and systolic arterial pressure in young normotensive subjects with family history of hypertension]. / Correlazione tra calciuria e pressione arteriosa sistolica in giovani normotesi con familiarità ipertensiva.

Many experimental evidences suggest an important role of calcium in the pathophysiology of essential hypertension; an increased calciuria could be a feature of these patients. Provocative tests, such as cold pressor test or aerobic exercise, have been proposed to be predictive for the occurrence of essential hypertension. Aim of this study has been to show a relation between sodium, calcium and potassium urinary excretion and blood pressure response to provocative tests in young normotensives with a positive parental history for essential hypertension. The subjects of the study were 59 young normotensive volunteers, 30 with a positive and 29 with a negative parental history for essential hypertension. All subjects underwent a cold pressor test and a maximal aerobic exercise on a bicycle ergometer; blood pressure and heart rate were recorded before, during and after the tests by means of an automatic device. An overnight urine collection allowed the evaluation of sodium, potassium and calcium excretion. There was no difference between the two groups as to blood pressure response to provocative tests or to urinary electrolyte excretion. Only in subjects with a positive parental history for essential hypertension there was linear correlation between calcium urinary excretion and systolic blood pressure, both baseline and exercise-induced.